Vitamin D Insufficiency Predictive of Paclitaxel-Induced Peripheral Neuropathy in Early-Stage Breast Cancer

Baseline vitamin D insufficiency may be a prognostic factor for increased risk of chemotherapy-induced peripheral neuropathy (CIPN) in patients receiving paclitaxel to treat early-stage breast cancer, according to a retrospective validation analysis of patients enrolled in the SWOG 0221 trial (NCT00070564).^1,2 Moreover, these findings may be especially meaningful for Black patients with breast cancer, as the results demonstrated that vitamin D insufficiency is more prevalent in this patient population.¹

The findings, which were presented in a poster by Lidia Schapira, MD, FASCO, professor of medicine at Stanford University School of Medicine, during the 2022 ASCO Annual Meeting, showed that patients with vitamin D insufficiency demonstrated a higher risk of CIPN.

Vitamin D insufficiency was defined as 20 ng/mL with higher levels signifying vitamin D sufficient status. Overall, the rate of grade 3/4 CIPN was 21% (n = 397) among patients with sufficient status compared with 14% (n = 794) among those with vitamin D insufficiency (odds ratio [OR], 1.57; 95% CI, 1.14-1.15; P = .005). After adjusting for covariates, the odds ratio was 1.39 (95% CI, 0.98-1.97; P = .066).¹

Notably, the findings also revealed that Black patients had a higher incidence of vitamin D insufficiency, which may correlate with higher incidence of CIPN. Compared with White patients enrolled in SWOG 0221, 77% of Black patients (n = 109) had vitamin D insufficiency compared with 28% of White patients (n = 997).¹

The rate of grade 3/4 CIPN among Black patients with vitamin D insufficiency (n = 84) was 31%. these patients were also less likely to be taking vitamin D supplements (P =.046). In an analysis comparing the association of vitamin D insufficiency with incidence of CIPN among Black patients vs White patients the odds ratio was 2.48 (95% CI, 1.57-3.86; P < .001).

“Chemotherapy-induced peripheral neuropathy is the major treatment-limiting and debilitating toxicity of paclitaxel,” the study authors wrote in the poster. “Prior retrospective studies suggest vitamin D insufficiency is associated with higher risk and severity of paclitaxel-induced [peripheral neuropathy].”

SWOG 0221 was a phase 3 trial evaluating paclitaxel-containing chemotherapy therapy dosing schedules in patients with high-risk early-stage breast cancer.2 Patients included in the retrospective study were women with banked serum who received at least 6 weeks of paclitaxel dosing throughout their treatment. In terms of paclitaxel administration, patients either received 80 mg/m2 weekly for 12 weeks or 1275 mg/m2 every 2 weeks for 6 weeks.^1,2

Participants were evaluated at baseline for 25-OH-vitamin D (D2+D3) via LC-MS assay. Investigators used logistic regression to identify the association between vitamin D insufficiency and grade 3 or greater sensory neurotoxicity. Results were adjusted for paclitaxel regimen assignment, age, self-reported race, and body mass index.¹

Among the 1191 enrolled patients, 195 (16%) experienced CIPN, 397 (33%) and had vitamin D insufficiency. Before initiating treatment, 66% of White patients were taking vitamin D supplements compared with 64% of Black patients (P = .791). During treatment, those numbers dropped to 58% and 42%, respectively (P = .046).

According to study authors, vitamin D promotes the syntheses and or neuronal growth factor and stimulates axon regeneration and myelination in animal models.1 Previous reports have shown that patients with lower vitamin D have experienced increased risk of CIPN as a result of treatment with neurotoxic agents. Further, vitamin D supplements have been associated with favorable results in treating diabetic neuropathy.¹

These findings provide multiple takeaways for providers seeking to improve their clinical practice, Schapira said, including the illumination of the value of thorough and standardized baseline measurements.

“We need to be more rigorous with measurements and the definitions. It is very important to have [uniform] baseline measurements,” she said. “I was very impressed [with the SWOG investigators] and I certainly know that most of my colleagues do not do such detailed physical exams before they see a patient who is about to [receive a] taxane in their practice. [This was] well done.”

Second, the investigators behind this study initially sought to identify the relationship between vitamin D and CIPN and identified that this relationship is greater within specific populations, reinforcing the importance of clinical research with an “equity lens,” Schapira said.

“Apply the equity lens to all clinical research,” she noted. “There should not just be research on equity—we should apply the equity lens to everything we do.”

Next steps for this research will include animal studies and prospective clinical trials aimed at evaluating the efficacy of vitamin D supplements as prophylaxis for CIPN. Investigators will also seek to expand their definition of CIPN by monitoring different CIPN subtypes and including patient-reported outcomes data.

References

1. Chen CS, McCann SE, Budd GT, et al. Vitamin D insufficiency as a peripheral neuropathy risk factor in White and Black patients in SWOG 0221. J Clin Oncol. 2022;40(suppl 16):12023. doi:10.1200/JCO.2022.40.16_suppl.12023

2. Budd G, Barlow WE, Moore HCF, et al. SWOG S0221: a phase III trial comparing chemotherapy schedules in high-risk early-stage breast cancer. J Clin Oncol.2015;33(1):58-64. doi:10.1200/JCO.2014.56.3296